2-氨基-4′-氯-二苯甲酮的合成新法

邻苯二甲酸酐与氯苯进行付-克反应得到羧酸。然后经酰氯化。酰胺化制得2-对氯苯甲酰基苯甲酰胺，最后经霍夫曼降解合成2-氨基-4′-氯-二苯甲酮。反应条件温和。操作简便，收率78.3%。     

4-(4-氯苯基)-3-甲基-2,4-二氧代丁酸乙酯的合成

对氯苯丙酮经烯胺化得4-[（Z）-1-（4-氯苯基）丙烯基]吗啉，再与草酰氯单乙酯缩合得利莫那班合成中间体4-（4-氯苯基）-3-甲基-2-4-二氧代丁酸乙酯，纯度91％，粗收率66％。     

富马酸卢帕他定的合成

以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。     

抗癌新药L-651582的合成

3,5-二氯苯甲酸经还原、TBDMSCl硅醚保护、酰化、脱保护和氯化制得3,5-二氯-4-（4-氯苯甲酰基）氯苄，再经叠氮化、与氰乙酰胺环合制得抗癌新药L-651582，总收率32％。     

盐酸洛哌丁胺的合成

苯乙腈经溴化、傅-克反应得到二苯基乙腈(2)。2经与环氧乙烷反应,以36%溴化氢冰醋酸溶液开环得4-溴-2,2-二苯基丁酸(4)。后者的酰氯与二甲胺反应,续与4-对氯苯基-4-羟基哌啶(7)缩合以及成盐,得盐酸洛哌丁胺。收率58%(以7计)。     

3,4-二氟苯甲腈的制备

价廉易得的对氯苯甲腈经硝化、氟交换制得4-氟-3-硝基苯甲腈,再经还原、重氮化,最后经schiemann反应得剑中间体3,4-二氟苯甲腈,总收率约48%.     

科研文摘

α-异丙基-4-氯苯乙酸的氢氧化钠溶液,在铜粉催化下于180°C反应8～10h,经处理即得标题化合物(是合成氟氰     

苯扎贝特的相转移催化法合成

对氯苯甲酰氯和对羟基苯乙胺反应制得N-(4-羟基苯乙基)-4-氯苯甲酰胺,再在相转移催化剂TEBA作用下、氢氧化钠溶液中加丙酮和氯仿反应制得降血脂药苯扎贝特,总收率约67%。     

(+)-氯吡格雷的合成工艺改进

目的改进抗血栓药物氯吡格雷硫酸氢盐的合成工艺。方法以(±)-邻氯苯甘氨酸为原料,经拆分、酯化,得到( )-邻氯苯甘氨酸甲酯,再与2-(2-噻吩基)乙醇对甲苯磺酸酯经SN2取代,生成α-2-噻吩乙氨基-2-氯苯基乙酸甲酯,后者在甲醛存在下环合制得( )-氯吡格雷游离碱,最后与硫酸成盐,经重结晶得目标产物氯吡格雷硫酸氢盐。结果与结论以26.9%的收率合成了目标产物,较大幅度地降低了生产成本,优化了反应条件,简化了后处理过程,适合于工业化生产。     

盐酸西布曲明的合成

对氯苯乙腈与1,3-二溴丙烷反应得到1－对氯苯基环丁腈,然后经格式反应后直接还原,再经N,N－二甲基化即可得西布曲明游离碱,成盐后即得盐酸西布曲明,总收率为51.9％。     

抗髓过氧化物酶抗体阳性韦格纳肉芽肿病肺损害的临床分析

目的提高对抗髓过氧化物酶（MPO）抗体阳性的韦格纳肉芽肿（WG）病患者的肺损害的认识。方法自2002年3月至2008年1月,对确诊的8例有肺损害的韦格纳肉芽肿病患者的临床表现、实验室检查、影像学特点进行回顾性分析并结合文献进行复习。结果8例患者中,男4例、女4例,平均49.83岁。抗MPO抗体阳性4例,抗蛋白酶3（PR3）抗体阳性4例。抗MPO抗体阳性的WG患者,临床表现为发热4例,咳嗽、咳痰4例、咯血2例、呼吸困难1例、哮喘样发作1例;4例均累及上呼吸道和肾脏;胸部CT显示双肺单发或多发结节影2例、肿块影1例,双肺弥漫斑片影或磨玻璃影4例,肺实变影1例,结节性空洞1例及支气管扩张2例。误诊为肺癌、肺结核、军团菌肺炎、真菌性肺炎者各1例。结论在国人的WG患者中,抗MPO抗体阳性可能并不少见。对临床表现为发热、肺部阴影伴抗MPO抗体阳性的患者应考虑WG的可能。     

Comparative toxicity of 4-chlorobiphenyl and its metabolite 4-chloro-4'-biphenylol in isolated rat liver mitochondria

4-Chlorobiphenyl (4-CB) is converted by the microsomal cytochrome P-450 system to its hydroxylated metabolite 4-chloro-4'-biphenylol (4'-OH-4-CB). A study of the effects of 4-CB and 4'-OH-4-CB on the energy-linked functions of rat liver mitochondria was carried out. 4'-OH-4-CB was more effective than 4-CB in causing the inhibition of state 3 respiration of mitochondria with both succinate and glutamate/malate. As a substrate specificity, with glutamate/malate the inhibition by each compound (ID50, 30 microM for 4'-OH-4-CB, 76 microM for 4.CB) was more significant than that with succinate (ID50, 200 microM for 4'-OH-4-CB, never reached 50% for 4-CB). From the effects on DNP-stimulated respiration, it was indicated that the electron transport from both glutamate/malate and succinate to oxygen was more sensitively inhibited by 4'-OH-4-CB than by 4-CB, with the same substrate specificity as for state 3 respiration (i.e. the inhibition by both compounds was greater with glutamate/malate than with succinate). Since there existed a good coincidence in the inhibition between state 3 and DNP-stimulated respiration with both substrates, the inhibition of state 3 respiration by both compounds was due to the inhibition of the electron transport. With succinate, the uncoupling of oxidative phosphorylation by both compounds was observed, the extent of which was greater with 4'-OH-4-CB than with 4-CB, although the uncoupling by higher concentrations of 4'-OH-4-CB was masked because of the increased inhibition in respiration. With glutamate/malate, the uncoupling action of 4-CB was largely, while that of 4'-OH-4-CB was completely, masked by progressive respiratory inhibition. 4'-OH-4-CB was more effective than 4-CB in causing stimulation of latent ATPase in mitochondria. These results indicate that both 4-CB and 4'-OH-4-CB impair mitochondrial energy-transducing functions, but 4'-OH-4-CB is more effective than 4-CB in damaging these functions. Thus, the product of the metabolism is more biologically active than the parent compound. The impairment of energy-linked mitochondrial reactions by the metabolite as well as of the parent compound may be an important factor in the toxicity of 4-CB.     

不同方法制备的4型肺炎球菌多糖-白喉类毒素结合物的免疫原性比较

 目的  比较以1-氰基-4-二甲氨基吡啶四氟硼酸盐（1-cyano-4-dimethylamino pyridine tetrafluoroborate，CDAP）和溴化氰（cyanogen bromide，CNBr）为活化剂制备的4型肺炎球菌多糖（type 4 pneumococcal polysaccharide，PS4）-白喉类毒素（diphtheria toxoid，DT）结合物（PS4-DT）原液的免疫原性。方法  分别以CDAP或CNBr为活化剂，各制备1批PS4-DT原液，并对原液的相关质量指标进行检测。分别用2种PS4-DT原液，间隔2周皮下注射NIH小鼠3次，末次免疫1周后采集血清，用ELISA检测血清抗体水平，比较不同方法制备的2种PS4-DT原液的免疫原性。结果  2种PS4-DT原液的主要质量指标均符合相关规定的要求，结合PS4的含量分别为257.1和203.1 μg/ml。2种PS4-DT原液均可与PS4抗血清发生特异性反应。抑制ELISA检测显示，2种PS4-DT原液对PS4抗血清的抑制率均达到100%。2种PS4-DT原液免疫小鼠产生的抗PS4抗体水平相近，抗体几何平均滴度分别为970.06和844.49。 结论  不同种方法制备的2种PS4-DT原液在小鼠中的免疫原性相似，且均可诱导小鼠产生较高水平的抗体。     

4-Chloro-4'-biphenylol as an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation

4-Chloro-4'-biphenylol (4'-OH-4-CB), a metabolite of 4-chlorobiphenyl (4-CB), stimulated state 4 respiration and released oligomycin-inhibited state 3 respiration of rat liver mitochondria with succinate as the respiratory substrate. When glutamate/malate and beta-hydroxybutyrate were used as the substrates, however, 4'-OH-4-CB was ineffective on these parameters. This indicates that 4'-OH-4-CB uncouples oxidative phosphorylation with succinate, but not with glutamate/malate and beta-hydroxybutyrate. 4'-OH-4-CB severely inhibited 2,4-dinitrophenol (DNP)-stimulated respiration with glutamate/malate (ID50, 25 microM) and beta-hydroxybutyrate (ID50, 32 microM) because of the blockade of electron transfer between NADH and CoQ span, masking the uncoupling action of 4'-OH-4-CB. On the other hand, the inhibition of the respiration with succinate was only apparent at high 4'-OH-4-CB concentrations (ID50, 260 microM). 4'-OH-4-CB also inhibited the oxidation of NADH in submitochondrial particles (ID50, 35 microM). State 3 respiration was more intensely inhibited by 4'-OH-4-CB in the presence of either glutamate/malate (ID50, 23 microM) or beta-hydroxybutyrate (ID50, 26 microM) than that in the presence of succinate (ID50, 220 microM). Thus, 4'-OH-4-CB acts as both an uncoupler and an inhibitor of oxidative phosphorylation. The overall in vitro effect is to prevent ATP synthesis, which may be an important factor in the mechanism underlying the toxicity of 4-CB.     

Metabolic adaptations to ammonia-induced oxidative stress in leaves of the submerged macrophyte Vallisneria natans (Lour.) Hara

Ammonia (i.e. the total of NH(3) and NH(4)(+)) has been one of the main causes of the decline of macrophytes in fresh water. In order to study the effects of ammonia toxicity, plants of the submersed macrophyte Vallisneria natans (Lour.) Hara were treated with various concentrations of NH(4)Cl (0.1, 0.4, 1.2, 2 and 2.8mM) for 4 days or with 2mM NH(4)Cl for different lengths of time (12h, 1, 2, 4 and 8 days). The toxic effect and oxidative stress caused by NH(4)Cl resulted in a reduction of total chlorophyll (chlorophyll a and b) and an increase in the levels of reactive oxygen species (ROS) O(2)(-) and H(2)O(2), with an increased concentration of NH(4)Cl and duration of exposure. Meanwhile, weak chlorosis and water-soaked symptoms were observed in older leaves exposed to 2.8mM NH(4)Cl for 4 days. The activity of superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), ascorbate peroxidase (APX) and glutathione reductase (GR) was up-regulated in leaves treated with 1.2, 2 and 2.8mM NH(4)Cl for 4 days or with 2mM NH(4)Cl for 1, 2 and 4 days, when compared with controls. Among these enzymes, the activity of superoxide dismutase, ascorbate peroxidase and glutathione reductase was significantly up-regulated in plants treated with 0.4mM NH(4)Cl for 4 days, while they were down-regulated at 4 and 8 days from their peak values in leaves treated with 2mM NH(4)Cl. The content of ascorbic acid decreased significantly in leaves treated with 0.4-2.8mM NH(4)Cl for 4 days or with 2mM NH(4)Cl for 2-8 days. The content of total glutathione (tGSH; reduced and oxidized glutathione) increased in leaves treated with NH(4)Cl at 0.4, 1.2 and 2mM for 4 days or with 2mM NH(4)Cl at 1, 2 and 4 days, while tGSH was decreased below the level of controls by treatment with 2.8mM NH(4)Cl for 4 days or to the level of controls by treatment with 2mM NH(4)Cl for 8 days. However, the content of malondialdehyde (MDA) decreased with increased concentration of NH(4)Cl and duration of exposure. Results from staining with 3,3'-dimethoxybenzidine (DAB) further indicated that the level of H(2)O(2) and the activity of guaiacol peroxidase increased significantly in plants exposed to 2mM NH(4)Cl for 4 days. These results suggested that ammonia exerted its toxic effect on the growth of V. natans (Lour.) Hara, at least in part, by induction of oxidative stress and inhibition of photosynthesis. The decrease in the content of malondialdehyde is discussed.     

Beiträge zur Chemie des Indols,X; Synthesen eserin-ähnlicher Verbindungen,II. Thioeserin,das Thioanalogon des Eserins

Thioeserine, the Thioanalogue of Eserin From deoxyeseroline ( 4a ) 5-rhodanodeoxyeseroline ( 4b ) is generated by treatment with thiocyanogen. 4b gives thioeseroline ( 4c ) by reduction with LiAlH₄ and 4d is produced by reaction of 4c with methyl isocyanate.     

支气管哮喘患儿血液脂氧素A_4与白三烯C_4水平的变化

目的 了解不同严重程度支气管哮喘(哮喘)患儿血液脂氧素A4(LXA4)、白三烯C4(LTC4)水平的变化.方法 应用ELISA方法测定106例急性发作期轻、中、重度哮喘患儿血液LXA4、LTC4含量,并与40例正常健康儿童作对照.结果 轻、中、重度哮喘患儿血液LXA4水平显著高于对照组(P<0.01),中、重度哮喘患儿血液LXA4水平亦显著高于轻度哮喘患儿(P<0.01),重度哮喘患儿血液LXA4水平显著低于中度哮喘患JL(P<0.01).轻、中、重度哮喘患儿血液LTC4水平逐渐升高,均显著高于对照组(P<0.01).结论 重度哮喘患儿血液LXA4水平低于中度哮喘患儿,说明体内白三烯的天然生理拮抗物质LXA4不足是哮喘加重的原因之一.     

CCR7蛋白和 CXCR4蛋白表达水平与非小细胞肺癌患者的预后及相关性研究

目的：通过对比分析 CCR7蛋白、CXCR4蛋白在非小细胞肺癌组织中的表达水平探讨这两种趋化因子表达的相关性以及患者的预后与其相关性。方法选择2012年3月至2013年5月进行非小细胞肺癌治疗的患者72例,分别取每位患者的非小细胞肺癌组织,并且随机选择36例患者的正常组织,利用免疫组织化学技术分析 CCR7、CXCR4蛋白在两种类型组织中的表达情况,分析两者表达水平与患者一般资料的关系以及两者表达水平的关系,并且对 CCR7蛋白与 CXCR4蛋白高低表达水平的患者分别进行生存分析,进而探究 CCR7蛋白、CXCR4蛋白与患者预后的相关性。结果 CCR7蛋白与 CXCR4蛋白在非小细胞肺癌组织与正常组织中的表达水平差异有统计学意义（P ＜0.05）。CCR7蛋白、CXCR4蛋白在非小细胞肺癌患者肿瘤组织中表达水平与患者临床分期和有无淋巴结转移存在显著正相关（ P ＜0.05）,而与其他一般资料无相关性（ P ＞0.05）。对 CCR7蛋白与 CXCR4蛋白高低表达组患者进行生存分析结果,2组患者均高表达患者较低表达患者预后差。两种蛋白的表达水平呈现正相关性（ P ＜0.05）。结论 CCR7、CXCR4蛋白在非小细胞肺癌肿瘤组织中表达水平明显高于正常肺部组织,且两者表达水平均与患者临床分期和淋巴结转移呈正相关关系。CCR7、CXCR4表达呈正相关,且均高表达组患者的预后较低表达组差。     

Synthesis, antiviral, antituberculostic, and antibacterial activities of some novel, 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-(substituted imino)pyrimidines

A variety of novel 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-substituted imino) pyrimidines were synthesized by reacting 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-amino pyrimidines with different substituted aromatic aldehydes, coumarin chloroisatin. The 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-amino pyrimidines were synthesized by reacting 3-(4'-substituted phenyl)-1-(4-nitrophenyl)-2-propen-1-ones with guanine hydrochloride. 3-(4-Substituted phenyl)-1-(4-nitrophenyl)-2-propen-1-ones were synthesized by reacting 4-nitroacetophenone with different para-substituted aromatic aldehydes. Spectral data (IR, NMR, and mass spectra) confirmed the structures of the synthesized compounds. The synthesized compounds were investigated for their antiviral, antituberculostic, and antibacterial activities. The results of antiviral, antituberculostic, and antibacterial activities indicated that the synthesized compounds exhibited mild to potent activities compared to the respective reference standards.     

Synthesis and biological investigations of new thiazolidinone and oxadiazoline coumarin derivatives

Ethyl (coumarin-4-oxy)acetate 1 was prepared through the reaction of 4-hydroxycoumarin with ethyl bromoacetate. Compound 1 was allowed to react with hydrazine hydrate to produce coumarin-4-oxyacetic hydrazide 2. The synthesis of N-(arylidene and alkylidene)-coumarin-4-oxyacetic hydrazones 3-20 was performed. The preparation of 2-substituted-3-[(coumarin-4-oxy) acetamido]thiazolidinones 21-26 and 2-[(coumarin-4-oxy)methyl]-4-acetyl-5-substituted-delta2-1,3,4-oxadiazolines 27-33 was performed by the reaction of the hydrazones 3, 4, 7, 9, 12, 14 with mercaptoacetic acid and the hydrazones 3, 4, 5, 7, 12, 15, 16 with acetic anhydride, respectively. The antiviral activities, cytotoxicities and structure-activity relationship (SAR) towards different microorganisms of the prepared compounds were studied.